Genetic and Functional Analyses of SHANK2 Mutations Suggest a Multiple Hit Model of Autism Spectrum Disorders
Figure 2
SHANK2 mutations in patients with ASD.
A. A heterozygous deletion of SHANK2 was identified with the Illumina Human 1M-Duo SNP array in a patient with autism (AU038_3). The deletion spans 421 kb on chromosome 11q13.3, covers twelve exons of the human SHANK2 and is not present in the parents. Each dot shows Log R Ratio (LRR; in red) and B allele frequency (BAF; in green). QuantiSNP score is represented with a blue line and indicates the deletion size. B. Location of the CNV and sequence variants (from this study and Berkel et al. 2010) along the SHANK2 protein: in red the variations specific to ASD, in orange the variations shared by ASD and controls and in green the variations specific to controls [26]. The breakpoints of the SHANK2 deletion in AU038_3 are represented with a dotted line on the protein. Stars indicate the variants affecting conserved amino acids. C. A total of 40 variants were identified and variants affecting conserved amino acids in other SHANK proteins are enriched in patients with ASD (nconserved = 12 and nnon-conserved = 3) compared with controls (nconserved = 6 and nnon-conserved = 11) (Fisher's exact test 1-sided, P = 0.013, OR = 6.83, 95% IC = 1.19–53.40). D. The percentage of carriers of SHANK2 variants in patients with ASD and Controls. Variants affecting a conserved amino acid among the SHANK proteins are enriched in patients with ASD (nconserved = 29 and nnon-conserved = 822) compared with controls (nconserved = 16 and nnon-conserved = 1074) (Fisher's exact test 1-sided, P = 0.004, OR = 2.37, 95% CI = 1.23–4.70). Open squares and filled squares represent the non-conserved and conserved amino acids, respectively. ANK, Ankyrin repeat domain; SH3, Src homology 3 domain; PDZ, postsynaptic density 95/Discs large/zona occludens-1 homology domain; SAM, sterile alpha motif domain; BSR, brain specific region; H, homer binding site; D, dynamin binding site; C, cortactin binding site. The proline-rich region is represented as a horizontal gray line.
